A primary knowledge of normal mechanisms of immune tolerance to self constituents is required before the immunological events leading to autoimmunity can be understood. Much has been learned about T and B cell tolerance to membrane and secreted proteins in recent years, largely through the use of transgenic technology, but there is a gap in knowledge regarding normal mechanisms of immune tolerance to protein antigens of the nucleus. Yet the majority of autoantigens, like La/SS-B, targeted in a number of systemic autoimmune diseases including Sjogren's syndrome and systemic lupus erythematosus are composed of protein and localize to the nucleus. The highly conserved nature of these house-keeping proteins (and DNA) has hampered their study in relation to immune tolerance. Moreover, the pathways through which nuclear proteins become visible to the immune system may be fundamentally different from those of previously studied membrane and secreted self antigens. In order for tolerance and autoimmunity to nuclear antigens to be comprehended, a requirement for unraveling the etiology(ies) of systemic autoimmune disease(s), it is therefore imperative that nuclear proteins be studied as a special class of self antigen. To address these issues, B cell tolerance to the La nuclear antigen will be investigated as a paradigm for protein antigens of the nucleus. These studies will utilize mice transgenic for the human La (hLa) gene in its natural form to allow the study of La-specific B cells in environments where self antigen is either present or absent. By focusing on B cells that recognize human specific epitopes of the hLa neoself antigen, the existence and extent of tolerance to the hLa antigen in the B cell compartment will be determined. Both transgenic and homologous recombination technology will be used to clarify the nature of B cell tolerance to La and determine the mechanisms of its occurrence. These studies will advance our collective understanding of anti-nuclear autoimmunity underlying a constellation of rheumatic disorders.